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  • Review Article
  • Published:

Leukaemogenesis: more than mutant genes

A Corrigendum to this article was published on 02 March 2010

This article has been updated

Key Points

  • Acute leukaemias, arising from neoplastic transformation of uncommitted or partially committed haematopoietic stem cells, are characterized by recurring chromosomal aberrations and gene mutations that are crucial to disease pathogenesis.

  • The recurring chromosomal translocations in acute myeloid leukaemia (AML) result in the generation of chimeric fusion proteins that in many cases function as transcriptional regulators. These include AML1–ETO (generated by a translocation between chromosomes 8 and 21, t(8;21)); CBFB–MYH11 (generated by an inversion of chromosome 16, inv(16) or t(16;16)); PML–RARA (generated by t(15;17)); MOZ–CBP (generated by t(8;16)); MORF–CBP (generated by t(10;16)); MOZ–TIF2 (generated by inv(8)); and MLL fused with various partners (generated by t(11q23)). They contribute to leukaemogenesis, at least in part by causing transcriptional deregulation through epigenetic modifications.

  • Epigenetic modifications, including DNA methylation, DNA demethylation and histone changes, lead to the activation or repression of gene expression. Aberrant epigenetic changes occur frequently in acute leukaemias. Fusion genes resulting from chromosome translocations can be regulators or mediators of the epigenetic machinery.

  • MicroRNA (miRNA) regulation may also considerably contribute to leukaemogenesis. Some miRNAs function as oncogenes or tumour suppressor genes in acute leukaemias. miRNA signatures correlate with cytogenetic and molecular subtypes of acute leukaemias, and some miRNA signatures are associated with outcome or survival of acute leukaemias.

  • Not only do miRNAs function in an epigenetic manner by post-transcriptional regulation of target genes, but they can also be targets of the epigenetic machinery and effectors of DNA methylation and histone modifications. These functions might be involved in leukaemogenesis.

  • Although the genetic heterogeneity of acute leukaemias poses therapeutic challenges, drugs or small molecules that target components of the epigenetic machinery hold great promise in the treatment of leukaemias. The use of all-trans retinoic acid in the therapy of acute promyelocytic leukaemia is one of the best known and most successful examples of targeted therapy involved in epigenetic changes; progress has also been made in the clinical trials of histone deacetylase inhibitors and DNA methyltransferase inhibitors. However, more effective treatment strategies are needed.

Abstract

Acute leukaemias are characterized by recurring chromosomal aberrations and gene mutations that are crucial to disease pathogenesis. It is now evident that epigenetic modifications, including DNA methylation and histone modifications, substantially contribute to the phenotype of leukaemia cells. An additional layer of epigenetic complexity is the pathogenetic role of microRNAs in leukaemias, and their key role in the transcriptional regulation of tumour suppressor genes and oncogenes. The genetic heterogeneity of acute leukaemias poses therapeutic challenges, but pharmacological agents that target components of the epigenetic machinery are promising as a component of the therapeutic arsenal for this group of diseases.

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Figure 1: Leukaemia fusion proteins and epigenetic deregulation.
Figure 2: Involvement of miRNAs in acute leukaemia.

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Change history

  • 21 January 2010

    In table 2 on page 30 of the above article, the reference for miR–196a and miR–196b was mistakenly indicated as reference 103. Accordingly, this reference has been replaced with references 89, 104 and 108–110. This has been corrected in the HTML and PDF versions.

References

  1. Rowley, J. D. Chromosomal translocations: revisited yet again. Blood 112, 2183–2189 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Heim, S. & Mitelman, F. Cancer Cytogenetics (Wiley-Blackwell, Hoboken, NJ, 2009). A current, most comprehensive reference on chromosome abnormalities in cancer.

    Google Scholar 

  3. Dalla-Favera, R. et al. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl Acad. Sci. USA 79, 7824–7827 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Taub, R. et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc. Natl Acad. Sci. USA 79, 7837–7841 (1982). Cloning of the first translocation breakpoint revealed that one of the genes involved was a known oncogene.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rowley, J. D. Letter, A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293 (1973). This paper showed that the Philadelphia chromosome, a specific chromosomal abnormality associated with CML, was the result of a reciprocal translocation between chromosomes 9 and 22.

    Article  CAS  PubMed  Google Scholar 

  6. Heisterkamp, N. et al. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 306, 239–242 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. Groffen, J. et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36, 93–99 (1984).

    Article  CAS  PubMed  Google Scholar 

  8. Rowley, J. D. Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukaemia. Ann. Genet. 16, 109–112 (1973).

    CAS  PubMed  Google Scholar 

  9. Rowley, J. D., Golomb, H. M. & Dougherty, C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet 1, 549–550 (1977).

    Article  CAS  PubMed  Google Scholar 

  10. Erickson, P. et al. Identification of breakpoints in t(8;21) acute myelogenous leukaemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood 80, 1825–1831 (1992).

    CAS  PubMed  Google Scholar 

  11. Longo, L. et al. Rearrangements and aberrant expression of the retinoic acid receptor alpha gene in acute promyelocytic leukaemias. J. Exp. Med. 172, 1571–1575 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. de Thé, H. et al. The PML-RARa fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukaemia encodes a functionally altered RAR. Cell 66, 675–684 (1991).

    Article  PubMed  Google Scholar 

  13. Grignani, F. et al. Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815–818 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Lin, R. J. et al. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391, 811–814 (1998). This paper shows that the PML–RARA and PLZF–RARA fusion oncoproteins in APL result in transcriptional repression of retinoic acid target genes through recruitment of the N-CoR histone deacetylase complex. A molecular explanation for the clinical efficacy of ATRA in APL with the PML–RARA fusion was also provided.

    Article  CAS  PubMed  Google Scholar 

  15. Wang, J., Hoshino, T., Redner, R. L., Kajigaya, S. & Liu, J. M. ETO, fusion partner in t(8;21) acute myeloid leukaemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc. Natl Acad. Sci. USA 95, 10860–10865 (1998). This paper highlights the fact that the mechanism of transcriptional repression by the AML1–ETO fusion protein in AML is through recruitment of the N-CoR complex. This implies that effective inhibitors of such repressor complexes might provide therapeutic benefit in this subset of AML

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lutterbach, B. et al. ETO, a target of t(8;21) in acute leukaemia, interacts with the N-CoR and mSin3 co-repressors. Mol. Cell. Biol. 18, 7176–7184 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Amann, J. M. et al. ETO, a target of t(8;21) in acute leukaemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain. Mol. Cell. Biol. 21, 6470–6483 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huang, M. E. et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukaemia. Blood 72, 567–572 (1988). This paper showed the efficacy of ATRA in the treatment of patients with APL. It was the first example of genotype-specific treatment of translocation-associated AML.

    CAS  PubMed  Google Scholar 

  19. Warrell, R. P. Jr et al. Differentiation therapy of acute promyelocytic leukaemia with tretinoin (all-trans-retinoic acid). N. Engl. J. Med. 324, 1385–1393 (1991).

    Article  PubMed  Google Scholar 

  20. Ruthenburg, A. J., Li, H., Patel, D. J. & Allis, C. D. Multivalent engagement of chromatin modifications by linked binding modules. Nature Rev. Mol. Cell Biol. 8, 983–994 (2007).

    Article  CAS  Google Scholar 

  21. Vaissiere, T., Sawan, C. & Herceg, Z. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat. Res. 659, 40–48 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. He, L. & Hannon, G. J. MicroRNAs: small RNAs with a big role in gene regulation. Nature Rev. Genet. 5, 522–531 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Wu, W., Sun, M., Zou, G. M. & Chen, J. MicroRNA and cancer: Current status and prospective. Int. J. Cancer 120, 953–960 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Esquela-Kerscher, A. & Slack, F. J. Oncomirs - microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006).

    Article  CAS  Google Scholar 

  26. Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nature Rev. Cancer 6, 857–866 (2006).

    Article  CAS  Google Scholar 

  27. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Fabbri, M. et al. MicroRNAs and noncoding RNAs in haematological malignancies: molecular, clinical and therapeutic implications. Leukaemia 22, 1095–1105 (2008).

    Article  CAS  Google Scholar 

  29. Garzon, R. & Croce, C. M. MicroRNAs in normal and malignant haematopoiesis. Curr. Opin. Haematol. 15, 352–358 (2008).

    Article  CAS  Google Scholar 

  30. Kluiver, J., Kroesen, B. J., Poppema, S. & van den Berg, A. The role of microRNAs in normal haematopoiesis and haematopoietic malignancies. Leukaemia 20, 1931–1936 (2006).

    Article  CAS  Google Scholar 

  31. Yendamuri, S. & Calin, G. A. The role of microRNA in human leukaemia: a review. Leukaemia 23, 1257–1263 (2009).

    Article  CAS  Google Scholar 

  32. Frohling, S., Scholl, C., Gilliland, D. G. & Levine, R. L. Genetics of myeloid malignancies: pathogenetic and clinical implications. J. Clin. Oncol. 23, 6285–6295 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Renneville, A. et al. Cooperating gene mutations in acute myeloid leukaemia: a review of the literature. Leukaemia 22, 915–931 (2008).

    Article  CAS  Google Scholar 

  34. Mullighan, C. G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758–764 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. The American Association for Cancer Research Human Epigenome Task Force and the European Union, Network of Excellence, Scientific Advisory Board. Moving AHEAD with an international human epigenome project. Nature 454, 711–715 (2008).

  36. Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143–153 (2004).

    Article  CAS  Google Scholar 

  37. Melki, J. R., Vincent, P. C. & Clark, S. J. Concurrent DNA hypermethylation of multiple genes in acute myeloid leukaemia. Cancer Res. 59, 3730–3740 (1999).

    CAS  PubMed  Google Scholar 

  38. Garcia-Manero, G. et al. Epigenetics of acute lymphocytic leukaemia. Semin. Haematol. 46, 24–32 (2009).

    Article  CAS  Google Scholar 

  39. Wang, J., Saunthararajah, Y., Redner, R. L. & Liu, J. M. Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukaemia cells. Cancer Res. 59, 2766–2769 (1999).

    CAS  PubMed  Google Scholar 

  40. Lutterbach, B., Hou, Y., Durst, K. L. & Hiebert, S. W. The inv(16) encodes an acute myeloid leukaemia 1 transcriptional co-repressor. Proc. Natl Acad. Sci. USA 96, 12822–12827 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G. & Downing, J. R. AML1, the target of multiple chromosomal translocations in human leukaemia, is essential for normal fetal liver haematopoiesis. Cell 84, 321–330 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, Q. et al. Disruption of the Cbfa2 gene causes necrosis and haemorrhaging in the central nervous system and blocks definitive haematopoiesis. Proc. Natl Acad. Sci. USA 93, 3444–3449 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gelmetti, V. et al. Aberrant recruitment of the nuclear receptor co-repressor-histone deacetylase complex by the acute myeloid leukaemia fusion partner ETO. Mol. Cell. Biol. 18, 7185–7191 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu, S. et al. Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukaemia. Cancer Res. 65, 1277–1284 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Linggi, B. et al. The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumour suppressor in acute myeloid leukaemia. Nature Med. 8, 743–750 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Yang, G. et al. Transcriptional repression of the Neurofibromatosis-1 tumour suppressor by the t(8;21) fusion protein. Mol. Cell. Biol. 25, 5869–5879 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Borrow, J., Goddard, A. D., Sheer, D. & Solomon, E. Molecular analysis of acute promyelocytic leukaemia breakpoint cluster region on chromosome 17. Science 249, 1577–1580 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. de The, H., Chomienne, C., Lanotte, M., Degos, L. & Dejean, A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347, 558–561 (1990).

    Article  CAS  PubMed  Google Scholar 

  49. Kakizuka, A. et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukaemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 66, 663–674 (1991).

    Article  CAS  PubMed  Google Scholar 

  50. Chen, Z. et al. Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J. 12, 1161–1167 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Licht, J. D. et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukaemia associated with translocation (11;17). Blood 85, 1083–1094 (1995).

    CAS  PubMed  Google Scholar 

  52. Redner, R. L., Rush, E. A., Faas, S., Rudert, W. A. & Corey, S. J. The t(5;17) variant of acute promyelocytic leukaemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 87, 882–886 (1996).

    CAS  PubMed  Google Scholar 

  53. Licht, J. D. Reconstructing a disease: What essential features of the retinoic acid receptor fusion oncoproteins generate acute promyelocytic leukaemia? Cancer Cell 9, 73–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Villa, R. et al. Role of the polycomb repressive complex 2 in acute promyelocytic leukaemia. Cancer Cell 11, 513–525 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Zheng, P. Z. et al. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukaemia. Proc. Natl Acad. Sci. USA 102, 7653–7658 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mueller, B. U. et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukaemia by restoring PU.1 expression. Blood 107, 3330–3338 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang, Z. Y. & Chen, Z. Acute promyelocytic leukaemia: from highly fatal to highly curable. Blood 111, 2505–2515 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Nasr, R. et al. Eradication of acute promyelocytic leukaemia-initiating cells through PML-RARA degradation. Nature Med. 14, 1333–1342 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Niu, C. et al. Studies on treatment of acute promyelocytic leukaemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukaemia patients. Blood 94, 3315–3324 (1999).

    CAS  PubMed  Google Scholar 

  60. Nowak, D., Stewart, D. & Koeffler, H. P. Differentiation therapy of leukaemia: 3 decades of development. Blood 113, 3655–3665 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Linggi, B. E., Brandt, S. J., Sun, Z. W. & Hiebert, S. W. Translating the histone code into leukaemia. J. Cell Biochem. 96, 938–950 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Borrow, J. et al. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nature Genet. 14, 33–41 (1996). This paper highlights the involvement of a HAT in chromosomal translocations in AML, and provides evidence that disruption of chromatin-modifying enzymes is associated with leukaemogenesis.

    Article  CAS  PubMed  Google Scholar 

  63. Panagopoulos, I. et al. Fusion of the MORF and CBP genes in acute myeloid leukaemia with the t(10;16)(q22;p13). Hum. Mol. Genet. 10, 395–404 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Kitabayashi, I., Aikawa, Y., Nguyen, L. A., Yokoyama, A. & Ohki, M. Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. EMBO J. 20, 7184–7196 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Perez-Campo, F. M., Borrow, J., Kouskoff, V. & Lacaud, G. The histone acetyl transferase activity of monocytic leukaemia zinc finger is critical for the proliferation of haematopoietic precursors. Blood 113, 4866–4874 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Liang, J., Prouty, L., Williams, B. J., Dayton, M. A. & Blanchard, K. L. Acute mixed lineage leukaemia with an inv(8)(p11q13) resulting in fusion of the genes for MOZ and TIF2. Blood 92, 2118–2122 (1998).

    CAS  PubMed  Google Scholar 

  67. Deguchi, K. et al. MOZ-TIF2-induced acute myeloid leukaemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell 3, 259–271 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Sobulo, O. M. et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukaemia with a t(11;16)(q23;p13.3). Proc. Natl Acad. Sci. USA 94, 8732–8737 (1997). This paper highlights the involvement of a HAT in an MLL -associated leukaemia, and provided an early insight that alluded to transcriptional deregulation through histone and chromatin modifications as being important in MLL -mediated leukaemogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ziemin-van der Poel, S. et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukaemias. Proc. Natl Acad. Sci. USA 88, 10735–10739 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Thirman, M. J. et al. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukaemias with 11q23 chromosomal translocations. N. Engl. J. Med. 329, 909–914 (1993).

    Article  CAS  PubMed  Google Scholar 

  71. Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Rev. Cancer 7, 823–833 (2007).

    Article  CAS  Google Scholar 

  72. Dou, Y. & Hess, J. L. Mechanisms of transcriptional regulation by MLL and its disruption in acute leukaemia. Int. J. Haematol. 87, 10–18 (2008).

    Article  CAS  Google Scholar 

  73. Nakamura, T. et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol. Cell 10, 1119–1128 (2002). This paper shows that MLL is found in a large multiprotein complex, that the SET domain has histone methyltransferase (H3K4) activity and that this multiprotein complex associates with the promoter of target genes such as HOXA9.

    Article  CAS  PubMed  Google Scholar 

  74. Milne, T. A. et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol. Cell 10, 1107–1117 (2002). This paper shows that although the SET domain of MLL is an H3K4 methyltransferase associated with Hox gene activation, a leukaemogenic MLL fusion protein (MLL–AF9) that activates Hox expression had no effect on H3K4 methylation. This implies that the mechanism for MLL -fusion gene activation and leukaemogenesis is not merely through perturbation of H3K4 methylation.

    Article  CAS  PubMed  Google Scholar 

  75. Yokoyama, A. et al. The menin tumour suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123, 207–218 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Milne, T. A. et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc. Natl Acad. Sci. USA 102, 749–754 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yokoyama, A. & Cleary, M. L. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell 14, 36–46 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Faber, J. et al. HOXA9 is required for survival in human MLL-rearranged acute leukaemias. Blood 113, 2375–2385 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dorrance, A. M. et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J. Clin. Invest. 116, 2707–2716 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Popovic, R. & Zeleznik-Le, N. J. MLL: how complex does it get? J. Cell Biochem. 95, 234–242 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Zhang, W., Xia, X., Reisenauer, M. R., Haemnway, C. S. & Kone, B. C. Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner. J. Biol. Chem. 281, 18059–18068 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Bitoun, E., Oliver, P. L. & Davies, K. E. The mixed-lineage leukaemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16, 92–106 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Mueller, D. et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 110, 4445–4454 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Krivtsov, A. V. et al. H3K79 methylation profiles define murine and human MLL-AF4 leukaemias. Cancer Cell 14, 355–368 (2008). This paper highlights increased H3K79 methylation in a genome-wide analysis in a mouse model of MLL -fusion leukaemia ( MLL–AF4 ), and provides some evidence for the inhibition of H3K79 as a therapeutic strategy in leukaemias involving MLL fusions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hayashita, Y. et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 65, 9628–9632 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Uziel, T. et al. The miR-1792 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proc. Natl Acad. Sci. USA 106, 2812–2817 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Li, Z. et al. Distinct microRNA expression profiles in acute myeloid leukaemia with common translocations. Proc. Natl Acad. Sci. USA 105, 15535–15540 (2008). This paper shows that specific alterations in miRNA expression distinguish AMLs with common translocations and implies that the deregulation of specific miRNAs can have a role in the development of leukaemia with these associated genetic rearrangements.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Li, Z. et al. Consistent deregulation of gene expression between human and murine MLL rearrangement leukaemias. Cancer Res. 69, 1109–1116 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mi, S. et al. Aberrant overexpression and function of the mir-17-92 cluster in MLL-rearranged acute leukaemia. Proc. Natl Acad. Sci. USA (in the press).

  92. Fontana, L. et al. MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nature Cell Biol. 9, 775–787 (2007). This paper shows that miRNA 17-5p-20a–106a functions as a master gene complex interlinked with AML1 in a mutual negative feedback loop in the control of monocytopoiesis.

    Article  CAS  PubMed  Google Scholar 

  93. Garzon, R. et al. MicroRNA fingerprints during human megakaryocytopoiesis. Proc. Natl Acad. Sci. USA 103, 5078–5083 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ventura, A. et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132, 875–886 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Koralov, S. B. et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 132, 860–874 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nature Immunol. 9, 405–414 (2008).

    Article  CAS  Google Scholar 

  97. Sylvestre, Y. et al. An E2F/miR-20a autoregulatory feedback loop. J. Biol. Chem. 282, 2135–2143 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. O'Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Woods, K., Thomson, J. M. & Hammond, S. M. Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. J. Biol. Chem. 282, 2130–2134 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Bruchova, H., Yoon, D., Agarwal, A. M., Mendell, J. & Prchal, J. T. Regulated expression of microRNAs in normal and polycythemia vera erythropoiesis. Exp. Haematol. 35, 1657–1667 (2007).

    Article  CAS  Google Scholar 

  101. Masaki, S., Ohtsuka, R., Abe, Y., Muta, K. & Umemura, T. Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis. Biochem. Biophys. Res. Commun. 364, 509–514 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Georgantas, R. W., 3rd. et al. CD34+ haematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control. Proc. Natl Acad. Sci. USA 104, 2750–2755 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Costinean, S. et al. Pre-B cell proliferation and lymphoblastic leukaemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc. Natl Acad. Sci. USA 103, 7024–7029 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Jongen-Lavrencic, M., Sun, S. M., Dijkstra, M. K., Valk, P. J. & Lowenberg, B. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukaemia. Blood 111, 5078–5085 (2008). This paper revealed distinctive miRNA signatures that correlate with cytogenetic and molecular subtypes of AMLs.

    Article  CAS  PubMed  Google Scholar 

  105. Garzon, R. et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukaemia. Blood 111, 3183–3189 (2008). This paper showed that miRNA expression was closely associated with selected cytogenetic and molecular abnormalities (for example, t(11q23), isolated trisomy 8, and FLT3 -ITD) and expression of some miRNAs (for example, miR-191 and miR-199a) was associated with survival of patients with AML.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Garzon, R. et al. Distinctive microRNA signature of acute myeloid leukaemia bearing cytoplasmic mutated nucleophosmin. Proc. Natl Acad. Sci. USA 105, 3945–3950 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. O'Connell, R. M. et al. Sustained expression of microRNA-155 in haematopoietic stem cells causes a myeloproliferative disorder. J. Exp. Med. 205, 585–594 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Schotte, D. et al. Identification of new microRNA genes and aberrant microRNA profiles in childhood acute lymphoblastic leukaemia. Leukaemia 23, 313–322 (2009).

    Article  CAS  Google Scholar 

  109. Popovic, R. et al. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood 113, 3314–3322 (2009). This paper suggests a mechanism whereby increased expression of miR-196b by MLL fusion proteins significantly contributes to leukaemia development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Velu, C. S., Baktula, A. M. & Grimes, H. L. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood 113, 4720–4728 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Johnson, S. M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Mayr, C., Haemann, M. T. & Bartel, D. P. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315, 1576–1579 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Garzon, R. et al. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukaemia. Oncogene 26, 4148–4157 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Calin, G. A. et al. Frequent deletions and downregulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukaemia. Proc. Natl Acad. Sci. USA 99, 15524–15529 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cimmino, A. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl Acad. Sci. USA 102, 13944–13949 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhao, H., Kalota, A., Jin, S. & Gewirtz, A. M. The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human haematopoietic cells. Blood 113, 505–516 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dixon-McIver, A. et al. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia. PLoS ONE 3, e2141 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Marcucci, G. et al. Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukaemia with high-risk molecular features: a Cancer and Leukaemia Group B Study. J. Clin. Oncol. 26, 5078–5087 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Marcucci, G. et al. MicroRNA expression in cytogenetically normal acute myeloid leukaemia. N. Engl. J. Med. 358, 1919–1928 (2008). This paper reports that a miRNA signature is associated with the clinical outcome of adults under the age of 60 years who have cytogenetically normal AML and high-risk molecular features.

    Article  CAS  PubMed  Google Scholar 

  120. Mi, S. et al. MicroRNA expression signatures accurately discriminate acute lymphoblastic leukaemia from acute myeloid leukaemia. Proc. Natl Acad. Sci. USA 104, 19971–19976 (2007). This paper shows that expression signatures of as few as two miRNAs can accurately discriminate ALL from AML.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zanette, D. L. et al. miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukaemia. Br. J. Med. Biol. Res. 40, 1435–1440 (2007).

    Article  CAS  Google Scholar 

  122. Fazi, F. et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 12, 457–466 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Saumet, A. et al. Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukaemia. Blood 113, 412–421 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Roman-Gomez, J. et al. Epigenetic regulation of microRNAs in acute lymphoblastic leukaemia. J. Clin. Oncol. 27, 1316–1322 (2009). This paper highlights that aberrant methylation affecting miRNA genes is a common phenomenon in ALL that affects the clinical outcome of these patients.

    Article  CAS  PubMed  Google Scholar 

  125. Sinkkonen, L. et al. MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nature Struct. Mol. Biol. 15, 259–267 (2008).

    Article  CAS  Google Scholar 

  126. Benetti, R. et al. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nature Struct. Mol. Biol. 15, 268–279 (2008).

    Article  CAS  Google Scholar 

  127. Garzon, R. et al. MicroRNA-29b induces global DNA hypomethylation and tumour suppressor gene reexpression in acute myeloid leukaemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113, 6411–6418 (2009). This paper shows that miR-29b targets DNMTs, thereby resulting in global DNA hypomethylation and reexpression of hypermethylated, silenced genes in AML.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kitamura, K. et al. Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid. Br. J. Haematol. 108, 696–702 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Amin, H. M., Saeed, S. & Alkan, S. Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17). Br. J. Haematol. 115, 287–297 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. He, L. Z. et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukaemia. J. Clin. Invest. 108, 1321–1330 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. He, L. Z.e.a. Distinct interactions of PML-RAR-alpha and PLZF-RAR-alpha with co-repressors determine differential responses to RA in APL. Nature Genet. 18, 126 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. Gozzini, A., Rovida, E., Dello Sbarba, P., Galimberti, S. & Santini, V. Butyrates, as a single drug, induce histone acetylation and granulocytic maturation: possible selectivity on core binding factor-acute myeloid leukaemia blasts. Cancer Res. 63, 8955–8961 (2003).

    CAS  PubMed  Google Scholar 

  133. Klisovic, M. I. et al. Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells. Leukaemia 17, 350–358 (2003).

    Article  CAS  Google Scholar 

  134. Yang, G., Thompson, M. A., Brandt, S. J. & Hiebert, S. W. Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein. Oncogene 26, 91–101 (2007).

    Article  PubMed  CAS  Google Scholar 

  135. Warrell, R. P., Jr., He, L. Z., Richon, V., Calleja, E. & Pandolfi, P. P. Therapeutic targeting of transcription in acute promyelocytic leukaemia by use of an inhibitor of histone deacetylase. J. Natl Cancer Inst. 90, 1621–1625 (1998).

    Article  CAS  PubMed  Google Scholar 

  136. Gore, S. D. & Carducci, M. A. Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. Expert Opin. Investig. Drugs 9, 2923–2934 (2000).

    Article  CAS  PubMed  Google Scholar 

  137. Yoo, C. B. & Jones, P. A. Epigenetic therapy of cancer: past, present and future. Nature Rev. Drug Discov. 5, 37–50 (2006).

    Article  CAS  Google Scholar 

  138. Mann, B. S., Johnson, J. R., Cohen, M. H., Justice, R. & Pazdur, R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12, 1247–1252 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Byrd, J. C. et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukaemia and acute myeloid leukaemia. Blood 105, 959–967 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Garcia-Manero, G. et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukaemias and myelodysplastic syndromes. Blood 111, 1060–1066 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Gojo, I. et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukaemias. Blood 109, 2781–2790 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Cimino, G. et al. Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukaemia. Cancer Res. 66, 8903–8911 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Klimek, V. M. et al. Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukaemia or advanced myelodysplastic syndromes. Clin. Cancer Res. 14, 826–832 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Kuendgen, A. et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukaemia. Cancer 106, 112–119 (2006).

    Article  CAS  PubMed  Google Scholar 

  145. Kuendgen, A. et al. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 104, 1266–1269 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Odenike, O. M. et al. Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukaemia. Clin. Cancer Res. 14, 7095–7101 (2008). This paper showed that patients with CBF AML were particularly susceptible to the anti-leukaemic effects of the HDACI romidepsin, and this was associated with upregulation of AML1–ETO target genes. This work provided evidence to support the hypothesis that reversal of transcriptional repression mediated by AML1 fusion genes can be achieved in vivo with the use of a HDACI.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Raffoux, E., Chaibi, P., Dombret, H. & Degos, L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukaemia. Haematologica 90, 986–988 (2005).

    CAS  PubMed  Google Scholar 

  148. Karon, M. et al. 5-Azacytidine: a new active agent for the treatment of acute leukaemia. Blood 42, 359–365 (1973).

    CAS  PubMed  Google Scholar 

  149. Issa, J. P. & Kantarjian, H. M. Targeting DNA methylation. Clin. Cancer Res. 15, 3938–3946 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Silverman, L. R. et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukaemia group B. J. Clin. Oncol. 20, 2429–2440 (2002).

    Article  CAS  PubMed  Google Scholar 

  151. Kornblith, A. B. et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukaemia Group B study. J. Clin. Oncol. 20, 2441–2452 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. Kantarjian, H. et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106, 1794–1803 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Steensma, D. P. et al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J. Clin. Oncol. 27, 3842–3848 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Silverman, L. R. et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukaemia Group B. J. Clin. Oncol. 24, 3895–3903 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Blum, W. et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukaemia. J. Clin. Oncol. 25, 3884–3891 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Garcia-Manero, G. et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukaemia. Blood 108, 3271–3279 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Soriano, A. O. et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukaemia and myelodysplastic syndrome. Blood 110, 2302–2308 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Gore, S. D. et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 66, 6361–6369 (2006). This paper showed that clinical response to combined DNMT and HDAC inhibition was associated with reversal of CDKN2B or CDH1 promoter methylation and provided some evidence to support the hypothesis that the clinical activity of DNMT inhibitors and HDACIs is based on the reversal of epigenetic silencing of tumour suppressor genes.

    Article  CAS  PubMed  Google Scholar 

  159. Fandy, T. E. et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood 114, 2764–2773 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Issa, J. P. et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in haematopoietic malignancies. Blood 103, 1635–1640 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Maslak, P. et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Leukaemia 20, 212–217 (2006).

    Article  CAS  Google Scholar 

  162. Sudan, N. et al. Treatment of acute myelogenous leukaemia with outpatient azacitidine. Cancer 107, 1839–1843 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Daskalakis, M. et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 100, 2957–2964 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. Yang, A. S. et al. DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukaemia. Cancer Res. 66, 5495–5503 (2006).

    Article  CAS  PubMed  Google Scholar 

  165. Jiemjit, A. et al. p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage. Oncogene 27, 3615–3623 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Link, P. A., Baer, M. R., James, S. R., Jones, D. A. & Karpf, A. R. p53-inducible ribonucleotide reductase (p53R2/RRM5XXXXX2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukaemia. Cancer Res. 68, 9358–9366 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Palii, S. S., Van Emburgh, B. O., Sankpal, U. T., Brown, K. D. & Robertson, K. D. DNA methylation inhibitor 5-Aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol. Cell. Biol. 28, 752–771 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. 21, 103–107 (1999). This paper shows that in the preclinical setting, the synergistic interaction of demethylation followed by HDAC inhibition results in the reactivation of epigenetically silenced tumour suppressor genes in cancer cells.

    Article  CAS  PubMed  Google Scholar 

  169. Tong, A. W. & Nemunaitis, J. Modulation of miRNA activity in human cancer: a new paradigm for cancer gene therapy? Cancer Gene Ther. 15, 341–355 (2008).

    Article  CAS  PubMed  Google Scholar 

  170. Calin, G. A. et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukaemias. Proc. Natl Acad. Sci. USA 101, 11755–11760 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Volinia, S. et al. A microRNA expression signature of human solid tumours defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hossain, A., Kuo, M. T. & Saunders, G. F. Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol. Cell. Biol. 26, 8191–8201 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Yu, Z. et al. A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J. Cell Biol. 182, 509–517 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tan, J. et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 21, 1050–1063 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Herman, J. G. & Baylin, S. B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349, 2042–2054 (2003).

    Article  CAS  PubMed  Google Scholar 

  176. Bhaumik, S. R., Smith, E. & Shilatifard, A. Covalent modifications of histones during development and disease pathogenesis. Nature Struct. Mol. Biol. 14, 1008–1016 (2007).

    Article  CAS  Google Scholar 

  177. Look, A. T. Oncogenic transcription factors in the human acute leukaemias. Science 278, 1059–1064 (1997).

    Article  CAS  PubMed  Google Scholar 

  178. Pui, C. H. & Jeha, S. New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nature Rev. Drug Discov. 6, 149–165 (2007).

    Article  CAS  Google Scholar 

  179. Rowley, J. D. Chromosome translocations: dangerous liaisons revisited. Nature Rev. Cancer 1, 245–250 (2001).

    Article  CAS  Google Scholar 

  180. Haferlach, T., Bacher, U., Kern, W., Schnittger, S. & Haferlach, C. Diagnostic pathways in acute leukaemias: a proposal for a multimodal approach. Ann. Haematol. 86, 311–327 (2007).

    Article  Google Scholar 

  181. Deschler, B. & Lubbert, M. Acute myeloid leukaemia: epidemiology and aetiology. Cancer 107, 2099–2107 (2006).

    Article  PubMed  Google Scholar 

  182. Armstrong, S. A. & Look, A. T. Molecular genetics of acute lymphoblastic leukaemia. J. Clin. Oncol. 23, 6306–6315 (2005).

    Article  CAS  PubMed  Google Scholar 

  183. Pui, C. H., Relling, M. V. & Downing, J. R. Acute lymphoblastic leukaemia. N. Engl. J. Med. 350, 1535–1548 (2004).

    Article  CAS  PubMed  Google Scholar 

  184. Viswanathan, S. R., Daley, G. Q. & Gregory, R. I. Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Choong, M. L., Yang, H. H. & McNiece, I. MicroRNA expression profiling during human cord blood-derived CD34 cell erythropoiesis. Exp. Haematol. 35, 551–564 (2007).

    Article  CAS  Google Scholar 

  186. Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Kohlhaas, S. et al. Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J. Immunol. 182, 2578–2582 (2009).

    Article  CAS  PubMed  Google Scholar 

  188. Ceppi, M. et al. MicroRNA-155 modulates the interleukin-1 signalling pathway in activated human monocyte-derived dendritic cells. Proc. Natl Acad. Sci. USA 106, 2735–2740 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Costinean, S. et al. Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of Emicro-MiR-155 transgenic mice. Blood 114, 1374–1382 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Gore, S. D. et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukaemia. Clin. Cancer Res. 8, 963–970 (2002).

    CAS  PubMed  Google Scholar 

  191. Gore, S. D.e.a. Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndrome and acute myeloid leukaemia. Clin. Cancer Res. 7, 2330–2339 (2001).

    CAS  PubMed  Google Scholar 

  192. Giles, F. et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory haematologic malignancies. Clin. Cancer Res. 12, 4628–4635 (2006).

    Article  CAS  PubMed  Google Scholar 

  193. Garcia-Manero, G. et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukaemia. Blood 112, 981–989 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Silverman, L. R. et al. A Phase I Trial of the Epigenetic Modulators Vorinostat, in Combination with Azacitidine (azaC) in Patients with the Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML): A Study of the New York Cancer Consortium. Blood Abstr. 112, 1252–1252 (2008).

    Google Scholar 

  195. Odenike, O. M. et al. Phase I Study of belinostat (PXD101) plus azacitidine (AZC) in patients with advanced myeloid neoplasms. J. Clin. Oncol. Abstr. 26 (2008).

  196. Fiskus, W. et al. Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukaemia cells. Mol. Cancer Ther. 5, 3096–3104 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank M. B. Neilly and D. Spearmon for their assistance in the preparation of the manuscript. This work was partly supported by the US National Institutes of Health CA127277 (J.C.) and CA118319 Subcontract (J.C.), the G. Harold and Leila Y. Mathers Charitable Foundation (J.C.), Leukaemia & Lymphoma Society Translational Research Grant (J.D.R.), the Spastic Paralysis Foundation of the Illinois, Eastern Iowa Branch of Kiwanis International (J.D.R.), American Society of Clinical Oncology Career Development Award (O.O.), and American Cancer Society Institutional Grant (O.O.).

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Correspondence to Janet D. Rowley.

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O.O. is listed as an inventor on a patent application (Histone deacetylase inhibitors and methods of use) that is owned by the University of Chicago Technology Office, USA, and is licensed to Gloucester Pharmaceuticals, USA. O.O. has received research support from MGI Pharma/Eisai, USA, and Topotarget, USA, and served on the advisory board for MGI Pharma.

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MiRNAs in Normal Hematopoiesis (PDF 182 kb)

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Expression pattern and potential function of miRNAs in leukemogenesis (PDF 343 kb)

Glossary

Chromosome translocation

A structural abnormality resulting from the rearrangement of pieces generally between two non-homologous chromosomes.

Acute leukaemia

A type of malignancy that results in the rapid growth of abnormal immature white blood cells (myeloid or lymphoid leukaemic blasts) in the bone marrow and blood and inhibition of normal haematopoiesis.

Histone deacetylase

An enzyme that regulates chromatin structure and function through the removal of the acetyl group from the lysine residues of core nucleosomal histones.

Histones

The chief protein components of chromatin, which have an important role in DNA packaging, chromosome stabilization and gene expression. Histones form the core component of nucleosomes.

Histone code

The 'rules' governing the pattern of covalent histone tail modifications. Histone tail modifications have an important role in the chromatin structure, and thereby in the regulation of gene expression.

Normal haematopoiesis

A developmental process by which all types of blood cells are continuously produced by rare pluripotent self-renewing haematopoietic stem cells. In normal adults, haematopoiesis occurs primarily in the bone marrow and lymphatic tissues.

French-American-British (FAB) classification of AML

The classification system divides AML into eight subtypes, M0 to M7, on the basis of the type of cells from which the leukaemia developed and the maturity of the cells.

Short-term repopulating HSCs

Haematopoietic stem cells (HSCs) are composed of short-term repopulating (STR) and long-term repopulating (LTR) stem cells. STR HSCs can sustain the haematopoietic system for only a short term, whereas LTR HSCs can reconstitute haematopoiesis for life.

Antagomir oligos

A class of chemically engineered antisense oligonucleotides that are complementary to either the mature miRNAs or their precursors and are used to specifically inhibit the activity of endogenous miRNAs, probably through irreversibly binding them. Antagomirs are used experimentally to constitutively inhibit specific miRNAs.

Nucleosomes

The basic units of chromatin that consist of approximately 146 base pairs of DNA wound around an octameric core of histone proteins: an H3-H4 tetramer and two H2A-H2B dimers.

Leukaemic blasts

Abnormal immature white blood cells that are malignant (neoplastic). Typically found in the bone marrow and peripheral blood of patients with acute leukaemia.

Myelodysplastic syndrome

A group of clonal haematopoietic stem cell disorders characterized by cytopenias (low blood counts) and ineffective haematopoiesis, dysplasia in one or more myeloid cell lines, and an increased risk of transformation to AML.

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Chen, J., Odenike, O. & Rowley, J. Leukaemogenesis: more than mutant genes. Nat Rev Cancer 10, 23–36 (2010). https://doi.org/10.1038/nrc2765

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